tbuckley/cabot-search huggingface dataset:
Assessment of Medical and Public Assistance Expenditures and Employment Among US Adults With Cancer Diagnoses
Authors: David C. Grabowski, Anuraag R. Kansal, Dana P. Goldman, Darius N. Lakdawalla
Journal: JAMA Network Open (2023)

Importance Prior research suggests significant social value associated with increased longevity due to preventing and treating cancer. Other social costs associated with cancer, such as unemployment, public medical spending, and public assistance, may also be sizable. Objective To examine whether a cancer history is associated with receipt of disability insurance, income, employment, and medical spending. Design, Setting, and Participants This cross-sectional study used data from the Medical Expenditure Panel Study (MEPS) (2010-2016) for a nationally representative sample of US adults aged 50 to 79 years. Data were analyzed from December 2021 to March 2023. Exposure Cancer history. Main Outcomes and Measures The main outcomes were employment, public assistance receipt, disability, and medical expenditures. Variables for race, ethnicity, and age were used as controls. A series of multivariate regression models were used to assess the immediate and 2-year association of a cancer history with disability, income, employment, and medical spending. Results Of 39 439 unique MEPS respondents included in the study, 52% were female, and the mean (SD) age was 61.44 (8.32) years; 12% of respondents had a history of cancer. Individuals with a cancer history who were aged 50 to 64 years were 9.80 (95% CI, 7.35-12.25) percentage points more likely to have a work-limiting disability and were 9.08 (95% CI, 6.22-11.94) percentage points less likely to be employed compared with individuals in the same age group without a history of cancer. Nationally, cancer accounted for 505 768 fewer employed individuals in the population aged 50 to 64 years. A cancer history was also associated with an increase of $2722 (95% CI, $2131-$3313) in medical spending, $6460 (95% CI, $5254-$7667) in public medical spending, and $515 (95% CI, $337-$692) in other public assistance spending. Conclusions and Relevance In this cross-sectional study, a history of cancer was associated with increased likelihood of disability, higher medical spending, and decreased likelihood of employment. These findings suggest there may be gains beyond increased longevity if cancer can be detected and treated earlier.
Psychometric Performance of a Substance Use Symptom Checklist to Help Clinicians Assess Substance Use Disorder in Primary Care
Authors: Theresa E. Matson, Kevin A. Hallgren, Gwen T. Lapham, Malia Oliver, Xiaoming Wang, Emily C. Williams, Katharine A. Bradley
Journal: JAMA Network Open (2023)

Substance use disorders (SUDs) are underrecognized in primary care, where structured clinical interviews are often infeasible. A brief, standardized substance use symptom checklist could help clinicians assess SUD.To evaluate the psychometric properties of the Substance Use Symptom Checklist (hereafter symptom checklist) used in primary care among patients reporting daily cannabis use and/or other drug use as part of population-based screening and assessment.This cross-sectional study was conducted among adult primary care patients who completed the symptom checklist during routine care between March 1, 2015, and March 1, 2020, at an integrated health care system. Data analysis was conducted from June 1, 2021, to May 1, 2022.The symptom checklist included 11 items corresponding to SUD criteria in the Diagnostic and Statistical Manual for Mental Disorders (Fifth Edition) (DSM-5). Item response theory (IRT) analyses tested whether the symptom checklist was unidimensional and reflected a continuum of SUD severity and evaluated item characteristics (discrimination and severity). Differential item functioning analyses examined whether the symptom checklist performed similarly across age, sex, race, and ethnicity. Analyses were stratified by cannabis and/or other drug use.A total of 23 304 screens were included (mean [SD] age, 38.2 [5.6] years; 12 554 [53.9%] male patients; 17 439 [78.8%] White patients; 20 393 [87.5%] non-Hispanic patients). Overall, 16 140 patients reported daily cannabis use only, 4791 patients reported other drug use only, and 2373 patients reported both daily cannabis and other drug use. Among patients with daily cannabis use only, other drug use only, or both daily cannabis and other drug use, 4242 (26.3%), 1446 (30.2%), and 1229 (51.8%), respectively, endorsed 2 or more items on the symptom checklist, consistent with DSM-5 SUD. For all cannabis and drug subsamples, IRT models supported the unidimensionality of the symptom checklist, and all items discriminated between higher and lower levels of SUD severity. Differential item functioning was observed for some items across sociodemographic subgroups but did not result in meaningful change (<1 point difference) in the overall score (0-11).In this cross-sectional study, a symptom checklist, administered to primary care patients who reported daily cannabis and/or other drug use during routine screening, discriminated SUD severity as expected and performed well across subgroups. Findings support the clinical utility of the symptom checklist for standardized and more complete SUD symptom assessment to help clinicians make diagnostic and treatment decisions in primary care.
PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth
Authors: Si Chen, Jiawei Chen, Wenting Du, Deanne M. Mickelsen, Hangchuan Shi, Han Yu, Sparsh Kumar, Chen Yan
Journal: Circulation Research (2023)

Background: Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX. Methods: We used global PDE10A knockout (KO) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies. Results: We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA (protein kinase A)- and cGMP/PKG-dependent signaling. Conclusions: Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.
Immune checkpoint-targeted drug conjugates: A promising tool for remodeling tumor immune microenvironment
Authors: Jiwoong Choi, Hochung Jang, Jiwon Choi, Yeonho Choi, Yoosoo Yang, Man Kyu Shim, Sun Hwa Kim
Journal: Journal of Controlled Release (2023)

Immune checkpoint blockade (ICB) therapy has shown remarkable outcomes along with multiple cases of complete regression in clinical practice. But unfortunately, most patients who have an immunosuppressive tumor immune microenvironment (TIME) respond poorly to these therapies. To improve the response rate of the patients, various treatment modalities that can boost cancer immunogenicity and remove immune tolerance have been combined with ICB therapies. However, the systemic administration of multiple immunotherapeutic agents can potentially cause severe off-target toxicities and immune-related adverse events, diminishing antitumor immunity and increasing the risk of additional complications. To address these problems, Immune Checkpoint-Targeted Drug Conjugates (IDCs) have been widely investigated for their ability to offer distinct advantages in remodeling the TIME for cancer immunotherapy. IDCs, consisting of immune checkpoint-targeting moieties, cleavable linkers, and payloads of immunotherapeutic agents, have a similar structure to conventional antibody-drug conjugates (ADCs) but target and block the immune checkpoint receptors, and then release the payloads conjugated through cleavable linkers. These unique mechanisms of IDCs prompt an immune-responsive TIME by modulating the multiple steps related to the cancer-immunity cycle, ultimately leading to tumor eradication. This review outlines the mode of action and advantages of IDCs. In addition, various IDCs for combinational immunotherapy are reviewed. Finally, the potential and challenges of IDCs for clinical translation are discussed.
The Importance of Symptom Reduction for Functional Improvement after Cognitive Behavioral Therapy for Anxiety and Depression: A Causal Mediation Analysis
Authors: Otto R F Smith, Leif E Aarø, Marit Knapstad
Journal: Psychotherapy and Psychosomatics (2023)

Introduction: The temporal relationship between symptoms and functioning in the context of cognitive behavioral therapy (CBT) for anxiety and depression is not fully understood, and there are few high-quality studies that have examined to what extent late intervention effects of CBT on functioning are mediated by initial intervention effects on symptoms while accounting for the initial effects on functioning and vice versa. Objective: The aim of the study was to investigate whether intervention effects on symptoms and functioning at 12-month follow-up were mediated by intervention effects on these outcomes at 6-month follow-up. Methods: Participants with anxiety and/or mild-to-moderate depression were randomly assigned to a primary mental health care service (n = 463) or treatment-as-usual (n = 215). Main outcomes were depressive symptoms (Patient Health Questionnaire [PHQ-9]), anxiety (General Anxiety Disorder-7 [GAD-7]), and functioning (Work and Social Adjustment Scale [WSAS]). Direct/indirect effects were derived using the potential outcomes and counterfactual framework. Results: The intervention effect on functioning at 12 months was largely explained by intervention effects at 6 months on depressive symptoms (51%) and functioning (39%). The intervention effect on depressive symptoms at 12 months was largely explained by the intervention effect at 6 months on depressive symptoms (70%) but not by functioning at 6 months. The intervention effect on anxiety at 12 months was only partly accounted for by intervention effects at 6 months on anxiety (29%) and functioning (10%). Conclusions: The findings suggest that late intervention effects of CBT on functioning were to a substantial degree explained by initial intervention effects on depressive symptoms even after accounting for initial effects on functioning. Our results support the importance of symptoms as an outcome in the context of CBT delivered in primary health care.
Association of rurality, socioeconomic status, and race with pancreatic cancer surgical treatment and survival
Authors: Gabriel A Brooks, Marisa R Tomaino, Niveditta Ramkumar, Qianfei Wang, Nirav S Kapadia, A James O’Malley, Sandra L Wong, Andrew P Loehrer, Anna N A Tosteson
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Pancreatectomy is a necessary component of curative intent therapy for pancreatic cancer, and patients living in nonmetropolitan areas may face barriers to accessing timely surgical care. We evaluated the intersecting associations of rurality, socioeconomic status (SES), and race on treatment and outcomes of Medicare beneficiaries with pancreatic cancer. Methods We conducted a retrospective cohort study, using fee-for-service Medicare claims of beneficiaries with incident pancreatic cancer (2016-2018). We categorized beneficiary place of residence as metropolitan, micropolitan, or rural. Measures of SES were Medicare–Medicaid dual eligibility and the Area Deprivation Index. Primary study outcomes were receipt of pancreatectomy and 1-year mortality. Exposure-outcome associations were assessed with competing risks and logistic regression. Results We identified 45 915 beneficiaries with pancreatic cancer, including 78.4%, 10.9%, and 10.7% residing in metropolitan, micropolitan, and rural areas, respectively. In analyses adjusted for age, sex, comorbidity, and metastasis, residents of micropolitan and rural areas were less likely to undergo pancreatectomy (adjusted subdistribution hazard ratio = 0.88 for rural, 95% confidence interval [CI] = 0.81 to 0.95) and had higher 1-year mortality (adjusted odds ratio = 1.25 for rural, 95% CI = 1.17 to 1.33) compared with metropolitan residents. Adjustment for measures of SES attenuated the association of nonmetropolitan residence with mortality, and there was no statistically significant association of rurality with pancreatectomy after adjustment. Black beneficiaries had lower likelihood of pancreatectomy than White, non-Hispanic beneficiaries (subdistribution hazard ratio = 0.80, 95% CI = 0.72 to 0.89, adjusted for SES). One-year mortality in metropolitan areas was higher for Black beneficiaries (adjusted odds ratio = 1.15, 95% CI = 1.05 to 1.26). Conclusions Rurality, socioeconomic deprivation, and race have complex interrelationships and are associated with disparities in pancreatic cancer treatment and outcomes.
Programmed antigen capture-harnessed dendritic cells by margination-hitchhiking lung delivery
Authors: Thi My Hue Huynh, Bhanu Nirosha Yalamandala, Min-Ren Chiang, Wei-Han Weng, Chien-Wen Chang, Wen-Hsuan Chiang, Lun-De Liao, Yu-Chen Liu, Shang-Hsiu Hu
Journal: Journal of Controlled Release (2023)
Chemo‐proteomics in antimalarial target identification and engagement
Authors: Brodie L. Bailey, William Nguyen, Alan F. Cowman, Brad E. Sleebs
Journal: Medicinal Research Reviews (2023)

Abstract Humans have lived in tenuous battle with malaria over millennia. Today, while much of the world is free of the disease, areas of South America, Asia, and Africa still wage this war with substantial impacts on their social and economic development. The threat of widespread resistance to all currently available antimalarial therapies continues to raise concern. Therefore, it is imperative that novel antimalarial chemotypes be developed to populate the pipeline going forward. Phenotypic screening has been responsible for the majority of the new chemotypes emerging in the past few decades. However, this can result in limited information on the molecular target of these compounds which may serve as an unknown variable complicating their progression into clinical development. Target identification and validation is a process that incorporates techniques from a range of different disciplines. Chemical biology and more specifically chemo‐proteomics have been heavily utilized for this purpose. This review provides an in‐depth summary of the application of chemo‐proteomics in antimalarial development. Here we focus particularly on the methodology, practicalities, merits, and limitations of designing these experiments. Together this provides learnings on the future use of chemo‐proteomics in antimalarial development.
Therapeutic Equivalence of Biosimilar and Reference Biologic Drugs in Rheumatoid Arthritis
Authors: Bruna de Oliveira Ascef, Matheus Oliveira Almeida, Ana Cristina de Medeiros-Ribeiro, Danieli Castro Oliveira de Andrade, Haliton Alves de Oliveira Junior, Patrícia Coelho de Soárez
Journal: JAMA Network Open (2023)

Importance Biosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA). Objectives To assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA. Data Sources MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021. Study Selection Head-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed. Data Extraction and Synthesis Two authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures Equivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire–Disability Index (HAQ-DI) (ie, SMD, −0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity. Results A total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ 2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, −0.04; 95% CrI, −0.11 to 0.02; τ 2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics. Conclusion and Relevance In this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.
Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection
Authors: Xi Zhang, Heng Xu, Jizhang Yu, Jikai Cui, Zhang Chen, Yuan Li, Yuqing Niu, Song Wang, Shuan Ran, Yanqiang Zou, Jie Wu, Jiahong Xia
Journal: Circulation (2023)

PCSK9 (proprotein convertase subtilisin/kexin 9), which is mainly secreted by the liver, is not only a therapeutic target for hyperlipidemia and cardiovascular disease, but also has been implicated in the immune regulation of infections and tumors. However, the role of PCSK9 and the liver in heart transplant rejection (HTR) and the underlying mechanisms remain unclear.We assessed serum PCSK9 expression in both murine and human recipients during HTR and investigated the effect of PCSK9 ablation on HTR by using global knockout mice and a neutralizing antibody. Moreover, we performed multiorgan histological and transcriptome analyses, and multiomics and single-cell RNA-sequencing studies of the liver during HTR, as well. We further used hepatocyte-specific Pcsk9 knockout mice to investigate whether the liver regulated HTR through PCSK9. Last, we explored the regulatory effect of the PCSK9/CD36 pathway on the phenotype and function of macrophages in vitro and in vivo.Here, we report that murine and human recipients have high serum PCSK9 levels during HTR. PCSK9 ablation prolonged cardiac allograft survival and attenuated the infiltration of inflammatory cells in the graft and the expansion of alloreactive T cells in the spleen. Next, we demonstrated that PCSK9 was mainly produced and significantly upregulated in the recipient liver, which also showed a series of signaling changes, including changes in the TNF-α (tumor necrosis factor α) and IFN-γ (interferon γ) signaling pathways and the bile acid and fatty acid metabolism pathways. We found mechanistically that TNF-α and IFN-γ synergistically promoted PCSK9 expression in hepatocytes through the transcription factor SREBP2 (sterol regulatory element binding protein 2). Moreover, in vitro and in vivo studies indicated that PCSK9 inhibited CD36 expression and fatty acid uptake by macrophages and strengthened the proinflammatory phenotype, which facilitated their ability to promote proliferation and IFN-γ production by donor-reactive T cells. Last, we found that the protective effect of PCSK9 ablation against HTR is dependent on the CD36 pathway in the recipient.This study reveals a novel mechanism for immune regulation by the liver through the PCSK9/CD36 pathway during HTR, which influences the phenotype and function of macrophages and suggests that the modulation of this pathway may be a potential therapeutic target to prevent HTR.
Patient-Reported Outcomes as Interradiographic Predictors of Response in Non–Small Cell Lung Cancer
Authors: Ambika S. Bhatt, Matthew B. Schabath, Aasha I. Hoogland, Heather S.L. Jim, Renee Brady-Nicholls
Journal: Clinical Cancer Research (2023)

Minimally invasive biomarkers have been used as important indicators of treatment response and progression in cancers such as prostate and ovarian. Unfortunately, all biomarkers are not prognostic in all cancer types and are often not routinely collected. Patient-reported outcomes (PRO) provide a non-obtrusive, personalized measure of a patient's quality of life and symptomatology, reported directly from the patient, and are increasingly collected as part of routine care. Previous literature has shown correlations between specific PROs (i.e., insomnia, fatigue) and overall survival. Although promising, these studies often only consider single time points and ignore patient-specific dynamic changes in individual PROs, which might be early predictors of treatment response or progression.In this study, PRO dynamics were analyzed to determine if they could be used as interradiographic predictors of tumor volume changes among 85 patients with non-small cell lung cancer undergoing immunotherapy. PRO questionnaires and tumor volume scans were completed biweekly and monthly, respectively. Correlation and predictive analysis were conducted to identify specific PROs that could accurately predict patient response.Changes in tumor volume over time were significantly correlated with dizziness (P < 0.005), insomnia (P < 0.05), and fatigue (P < 0.05). In addition, cumulative changes in insomnia could predict progressive disease with a 77% accuracy, on average 45 days prior to the next imaging scan.This study presents the first time that patient-specific PRO dynamics have been considered to predict how individual patients will respond to treatment. This is an important first step in adapting treatment to improve response rates.